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A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication

dc.contributor.authorYuzheng Zhou
dc.contributor.authorZongpeng Chen
dc.contributor.authorSijie Liu
dc.contributor.authorSixu Liu
dc.contributor.authorYujie Liao
dc.contributor.authorAshuai Du
dc.contributor.authorZijun Dong
dc.contributor.authorYongxing Zhang
dc.contributor.authorXuan Chen
dc.contributor.authorSiyi Tao
dc.contributor.authorXin Wu
dc.contributor.authorAroona Razzaq
dc.contributor.authorGang Xu
dc.contributor.authorDe-an Tan
dc.contributor.authorShanni Li
dc.contributor.authorYouwen Deng
dc.contributor.authorJian Peng
dc.contributor.authorShuyan Dai
dc.contributor.authorXu Deng
dc.contributor.authorXianwen Zhang
dc.contributor.authorTaijiao Jiang
dc.contributor.authorZheng Zhang
dc.contributor.authorGong Cheng
dc.contributor.authorJincun Zhao
dc.contributor.authorZanxian Xia
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Basic Medicine, School of Medicine, Hunan Normal University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of spine surgery, The Third Xiangya Hospital, Central South University
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherSchool of Basic Medical Sciences, Anhui Medical University
dc.contributor.otherHunan Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People’s Liberation Army of China (The Second Affiliated Hospital of Hunan Normal University)
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.contributor.otherDepartment of spine surgery, The Third Xiangya Hospital, Central South University
dc.contributor.otherDepartment of Geriatric Surgery, Xiangya Hospital, Central South University
dc.contributor.otherXiangya School of Pharmaceutical Sciences, Central South University
dc.contributor.otherXiangya School of Pharmaceutical Sciences, Central South University
dc.contributor.otherInstitute of Infectious Diseases, Shenzhen Bay Laboratory
dc.contributor.otherGuangzhou Laboratory
dc.contributor.otherInstitute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology
dc.contributor.otherInstitute of Infectious Diseases, Shenzhen Bay Laboratory
dc.contributor.otherInstitute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology
dc.contributor.otherDepartment of Cell Biology, School of Life Sciences, Central South University
dc.date.accessioned2024-06-30T11:33:52Z
dc.date.accessioned2025-10-08T08:34:27Z
dc.date.available2025-10-08T08:34:27Z
dc.date.issued01-06-2024
dc.identifier.urihttp://digilib.fisipol.ugm.ac.id/repo/handle/15717717/36066
dc.description.abstractAbstract The ORF9b protein, derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response. Despite its significance, the precise regulatory mechanisms underlying its function remain elusive. In the present study, we unveil that the ORF9b protein of SARS-CoV-2, including emerging mutant strains like Delta and Omicron, can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway, despite certain mutations present among these strains. Moreover, our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70 (TOM70) as a substrate receptor, bridging ORF9b with heat shock protein 90 alpha (HSP90α) and Cullin 5 (CUL5) to form a complex. Within this complex, CUL5 triggers the ubiquitination and degradation of ORF9b, acting as a host antiviral factor, while HSP90α functions to stabilize it. Notably, treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b, leading to a pronounced inhibition of SARS-CoV-2 replication. Single-cell sequencing data revealed an up-regulation of HSP90α in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90α to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90α complex as a critical regulator of ORF9b protein stability, shedding light on the intricate host–virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.
dc.language.isoEN
dc.publisherNature Publishing Group
dc.subject.lccMedicine
dc.titleA Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication
dc.typeArticle
dc.description.pages1-18
dc.description.doi10.1038/s41392-024-01874-5
dc.title.journalSignal Transduction and Targeted Therapy
dc.identifier.e-issn2059-3635
dc.identifier.oaioai:doaj.org/journal:72c1fb80cf934c1d91f4910ac813a63b
dc.journal.infoVolume 9, Issue 1


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